3-Substituted quinuclidines and their use

ABSTRACT

This invention relates to novel 3-substituted quinuclidine derivatives, which are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

TECHNICAL FIELD

This invention relates to novel 3-substituted quinuclidine derivatives,which are found to be cholinergic ligands at the nicotinic acetylcholinereceptors and modulators of the monoamine receptors and transporters.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

BACKGROUND ART

Nilsson et al. [Nilsson B M, Sundquist S, Johansson G, Nordvall G, GlasG, Nilvebrant L & Hacksell U; J. Med. Chem. 1995 38 473-487] describethe synthesis and muscarinic activity of certain 3-heteroarylsubstituted quinuclidin-2-ene derivatives including3-(2-benzofuranyl)quinuclidine-2-ene,3-(3-benzofuranyl)quinuclidine-2-ene,3-(2-benzothienyl)quinuclidine-2-ene,3-(3-benzothienyl)quinuclidine-2-ene,3-(2-benzoxazolyl)quinuclidine-2-ene,3-(2-benzthiazolyl)quinuclidine-2-ene, 3-(2-benzofuranyl)-quinuclidineand 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine.

Nordvall et al. [Nordvall G, Sundquist S, Johansson G, Glas G,Nilvebrant L & Hacksell U; J. Med. Chem. 1996 39 3269-3277] describe thesynthesis and muscarinic activity of certain quinuclidine-2-enederivatives including 3-(2-benzofuranyl)-quinuclidine-2-ene and3-(2-furo[3,2-b]pyridinyl)quinudidine-2-ene.

Johansson et al. [Johansson G, Sundquist S, Nordvall G, Nilsson B M,Brisander M, Nilvebrant L & Hacksell U; J. Med. Chem. 1997 40 3804-3819]describe the synthesis of certain quinuclidine-2-ene derivatives usefulas muscarinic antagonists.

WO 93/23395 (Kabi Pharmacia) describes heteroaromatic quinuclidinenesand their activity on muscarinic acetylcholine receptors.

However, the 3-substituted heteroaromatic quinuclidine derivatives ofthe present invention have never been disclosed.

SUMMARY OF THE INVENTION

The present invention is devoted to the provision of new quinuclidinederivatives that are modulators of the nicotinic and/or of the monoaminereceptors, and which modulators are useful for the treatment of diseasesor disorders related to the cholinergic receptors, and in particular thenicotinic acetylcholine receptor (nAChR), the serotonin receptor(5-HTR), the dopamine receptor (DAR) and the norepinephrine receptor(NER), and of the biogenic amine transporters for serotonin (5-HT),dopamine (DA) and norepinephrine (NE).

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

The compounds of the invention may also be useful as diagnostic tools ormonitoring agents in various diagnostic methods, and in particular forin vivo receptor imaging (neuroimaging), and they may be used inlabelled or unlabelled form.

Accordingly, in its first aspect the invention provides 3-substitutedquinuclidine derivatives represented by Formula I:

-   -   wherein    -   - - - - represents an optional double bond; and    -   R′ represents an indolyl group, a benzimidazolyl group or a        benzotriazolyl group, which heteroaryl group is optionally        substituted one or more times with alkyl, cycloalkyl,        cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,        alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl,        alkenoxy, alkoxyalkenyl, alkynyl, alkoxyalkynyl, alkynoxy,        alkylthio, alkylseleno, methylenedioxy,        trifluoromethanesulfonyloxy, halo, haloalkyl, hydroxy,        haloalkoxy, cyano, amino, nitro, oxime, alkyloxime, acyloxime,        aryl, heteroaryl, and/or a group of the formula —(CO)R⁴, —COOR⁴,        —O(CO)R⁴, —CONR³R⁴, —NH—CO₂R³, —NHCO—R³ or —OCO—NR³R⁴; in which        formulas R³ and R⁴ independently of one another represents        hydrogen or alkyl;    -   any of its enantiomers or any mixture of enantiomers, or a        pharmaceutically acceptable salt thereof, or an aza-onium-salt        thereof.

In a second aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a 3-substitutedquinuclidine derivative of the invention, or a pharmaceuticallyacceptable addition salt thereof, together with at least onepharmaceutically acceptable carrier or diluent.

Viewed from another aspect the invention relates to the use of a3-substituted quinuclidine derivative of the invention for thetreatment, prevention or alleviation of a disease or a disorder or acondition that is responsive to the action of a nicotinic acetylcholinereceptor modulator.

In yet another aspect the invention provides a method of the treatmentor alleviation of a disease or disorder of a living animal body,including a human, which disease or disorder is responsive to the actionof a nicotinic acetylcholine receptor modulator, which method comprisesthe step of administering to such a living animal body, including ahuman, in need thereof a therapeutically effective amount of the3-substituted quinuclidine derivative of the invention.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

3-Substituted Quinuclidine Derivatives

In its first aspect the invention provides novel 3-substitutedquinuclidine derivative represented by Formula I:

-   -   wherein    -   - - - - represents an optional double bond; and    -   R′ represents an indolyl group, a benzimidazolyl group or a        benzotriazolyl group, which heteroaryl group is optionally        substituted one or more times with alkyl, cycloalkyl,        cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,        alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl,        alkenoxy, alkoxyalkenyl, alkynyl, alkoxyalkynyl, alkynoxy,        alkylthio, alkylseleno, methylenedioxy,        trifluoromethanesulfonyloxy, halo, haloalkyl, hydroxy,        haloalkoxy, cyano, amino, nitro, oxime, alkyloxime, acyloxime,        aryl, heteroaryl, and/or a group of the formula —(CO)R⁴, —COOR⁴,        —O(CO)R⁴, —CONR³R⁴, —NH—CO₂R³, —NHCO—R³ or —OCO—NR³R⁴; in which        formulas R³ and R⁴ independently of one another represents        hydrogen or alkyl;    -   any of its enantiomers or any mixture of enantiomers, or a        pharmaceutically acceptable salt thereof, or an aza-onium-salt        thereof.

In a 1^(st) preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula II:

-   -   wherein    -   - - - - represents an optional double bond; and    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R²        or —OCO—NR²R³; in which formulas R² and R³ independently of each        another represents hydrogen or alkyl.

In a 2^(nd) preferred embodiment, the 3-substituted quinudidinederivative of the invention is a compound of Formula III:

-   -   wherein    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—C_(O) ₂R²,        —NHCO—R² or —OCO—NR²R³; in which formulas R² and R³        independently of each another represents hydrogen or alkyl.

In a more preferred embodiment the 3-substituted quinuclidine derivativeof the invention is a compound of Formula II or III wherein R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo, haloalkyl,hydroxy, haloalkoxy, cyano, amino, nitro or phenyl.

In an even more preferred embodiment the 3-substituted quinuclidinederivative of the invention is a compound of Formula II or III whereinR¹ and R², independently of one another, represent hydrogen, alkyl,alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitro or phenyl.

In a yet more preferred embodiment the 3-substituted quinuclidinederivative of the invention is a compound of Formula II or III whereinwherein one of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.

In a most preferred embodiment the 3-substituted quinuclidine derivativeof the invention is

-   3-(3-Indolyl)-quinuclidine-2-ene;-   3-(5-Bromo-3-indolyl)-quinuclidine-2-ene;-   3-(5-Methoxy-3-indolyl)-quinuclidine-2-ene;-   3-(5-Phenyl-3-indolyl)-quinuclidine-2-ene;    -   any of its enantiomers or any mixture of enantiomers, or a        pharmaceutically acceptable salt thereof, or an aza-onium-salt        thereof.

In a 3^(rd) preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula IV:

-   -   wherein    -   - - - - represents an optional double bond; and    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R²        or —OCO—NR²R³; in which formulas R² and R³ independently of each        another represents hydrogen or alkyl.

In a 4^(th) preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula V:

-   -   wherein    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R²        or —OCO—NR²R³; in which formulas R² and R³ independently of each        another represents hydrogen or alkyl.

In a more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula IV or V, wherein R¹and R², independently of one another, represent hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo,haloalkyl, hydroxy, haloalkoxy, cyano, amino, nitro or phenyl.

In an even more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula IV or V, wherein R¹and R², independently of one another, represent hydrogen, alkyl, alkoxy,halo, haloalkyl, hydroxy, cyano, amino, nitro or phenyl.

In a yet more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula IV or V, whereinone of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.

In a most preferred embodiment, the 3-substituted quinuclidinederivative of the invention is

-   (±)-3-(1-Benzimidazolyl)-quinuclidine;-   (±)-3-(2-Trifluoromethyl-1-benzimidazolyl)-quinuclidine; or-   (±)-3-(5-Trifluoromethyl-1-benzimidazolyl)-quinuclidine;    -   any of its enantiomers or any mixture of enantiomers, or a        pharmaceutically acceptable salt thereof, or an aza-onium-salt        thereof.

In a 5^(th) preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula VI:

-   -   wherein    -   - - - - represents an optional double bond; and    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R²        or —OCO—NR²R³; in which formulas R² and R³ independently of each        another represents hydrogen or alkyl.

In a 6^(th) preferred embodiment, the 3-substituted quinudidinederivative of the invention is a compound of Formula VIII:

-   -   wherein    -   R¹ and R², independently of one another, represent hydrogen,        alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,        cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy,        alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl,        hydroxy, cyano, amino, nitro, phenyl, and/or a group of the        formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R²        or —OCO—NR²R³; in which formulas R² and R³ independently of each        another represents hydrogen or alkyl.

In a more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula VI or VII, whereinR¹ and R², independently of one another, represent hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo,haloalkyl, hydroxy, haloalkoxy, cyano, amino, nitro or phenyl.

In an even more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula VI or VII, whereinR¹ and R², independently of one another, represent hydrogen, alkyl,alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitro or phenyl.

In a yet more preferred embodiment, the 3-substituted quinuclidinederivative of the invention is a compound of Formula VI or VII, whereinone of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.

In a most preferred embodiment, the 3-substituted quinuclidinederivative of the invention

-   (±)-3-(1-Benzotriazolyl)-quinuclidine;    -   any of its enantiomers or any mixture of enantiomers, or a        pharmaceutically acceptable salt thereof, or an aza-onium-salt        thereof.

Definition of Substituents

In the context of this invention halo represents fluorine, chlorine,bromine or iodine.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkenyl),more preferred of from two to six carbon atoms (C₂₋₆-alkenyl), includingat least one double bond. In a most preferred embodiment the alkenylgroup of the invention is ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or3-butenyl, or 1,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexdienyl, or 1,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or7-octenyl, or 1,3-octdienyl, or 1,3,5-octdienyl, or1,3,5,7-octtetraenyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkynyl),more preferred of rom two to six carbon atoms (C₂₋₆-alkynyl), includingat least one triple bond. In its most preferred embodiment the alkynylgroup of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentdiynyl;1-, 2-, 3-, 4-, or 5-henynyl, or 1,3-hexdiynyl or 1,3,5-hextriynyl; 1-,2-, 3-, 4-, 5- or 6-heptynyl, or 1,3-heptdiynyl, or 1,3,5-hepttriynyl;1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1,3-octdiynyl, or1,3,5-octtriynyl, or 1,3,5,7-octtetraynyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkoxy group designates an“alkyl-O-” group, wherein alkyl is as defined above, an alkenoxy groupdesignates an “alkenyl-O-” group, wherein alkenyl is as defined above,an alkynoxy group designates an “alkynyl-O-” group, wherein alkynyl isas defined above, an alkoxyalkyl group designates an “alkyl-O-alkyl”group, wherein alkyl is as defined above, an alkoxyalkenyl groupdesignates an “alkyl-O-alkenyl” group, wherein alkyl and alkenyl are asdefined above, an alkoxyalkynyl group designates an “alkyl-O-alkynyl”group, wherein alkyl and alkynyl are as defined above, a cycloalkoxygroup designates a “cycloalkyl-O-” group, wherein cycloalkyl is asdefined above, a alkoxycycloalkyl group designates a“alkyl-O-cycloalkyl-” group, wherein alkyl and cycloalkyl are as definedabove, and a cycloalkoxyalkoxy group designates a“cycloalkyl-O-alkyl-O-” group, wherein alkyl and cycloalkyl are asdefined above.

In the context of this invention an alkylthio group designates an“alkyl-S-” group (thioalkoxy), wherein alkyl is as defined above, analkenylthio group designates an “alkenyl-S-” group, wherein alkenyl isas defined above, and an alkynylthio group 35 designates an “alkynyl-S-”group, wherein alkynyl is as defined above.

In the context of this invention an alkylseleno group designates an“alkyl-Se-” group, wherein alkyl is as defined above, an alkenylselenodesignates an “alkenyl-Se-” group, wherein alkenyl is as defined above,and an alkynylseleno group designates an “alkynyl-Se-” group, whereinalkynyl is as defined above.

In the context of this invention an alkyloxime group designates a“C═N—O-alkyl” group, wherein alkyl is as defined above, and an acyloximegroup designates a “C═N—O—COOH” group or a “C═N—O—CO-alkyl” group,wherein alkyl is as defined above.

In the context of this invention an aryl group designates a monocyclicor polycyclic aromatic hydrocarbon group. Examples of preferred arylgroups of the invention include phenyl, indenyl, naphthyl, azulenyl,fluorenyl, and anthracenyl. In a most preferred embodiment the arylgroup of the invention is phenyl.

In the context of this invention a heteroaryl group designates a mono-,bi- or polycyclic aromatic compound, which holds one or more heteroatomsin its ring structure. Preferred heteroatoms include nitrogen (N),oxygen (O), and sulphur (S). Preferred heteroaryl groups of theinvention include the mono- and bi-cyclic heteroaryl groups.

Preferred monocyclic heteroaryl groups of the invention include aromatic5- and 6 membered heterocyclic monocyclic groups, including furanyl, inparticular 2- or 3-furanyl; thienyl, in particular 2 or 3-thienyl;pyrrolyl (azolyl), in particular 1,2 or 3-pyrrolyl; oxazolyl, inparticular oxazol-2,4 or 5-yl; thiazolyl, in particular thiazol-2,4 or5-yl; imidazolyl, in particular 1,2 or 4-imidazolyl; pyrazolyl, inparticular 1,3 or 4-pyrazolyl; isoxazolyl, in particular isoxazol-3, 4or 5-yl; isothiazolyl, in particular isothiazol-3,4 or 5-yl;oxadiazolyl, in particular 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazol-3,4or 5-yl; triazolyl, in particular 1,2,3-, 1,2,4-, 2,1,3- or4,1,2-triazolyl; thiadiazolyl, in particular thiadiazol-3,4 or 5-yl;pyridinyl, in particular 2,3 or 4-pyridinyl; pyridazinyl, in particular3 or 4-pyridazinyl; pyrimidinyl, in particular 2,4 or 5-pyrimidinyl;pyrazinyl, in particular 2 or 3-pyrazinyl; and triazinyl, in particular1,2,3-, 1,2,4- or 1,3,5-triazinyl.

Preferred bicyclic heteroaryl groups of the invention includeindolizinyl, in particular 2,5 or 6-indolizinyl; indolyl, in particular2,5 or 6-indolyl; isoindolyl, in particular 2,5 or 6-isoindolyl;benzo[b]furanyl, in particular 2,5 or 6-benzofuranyl; benzo[b]thienyl,in particular 2,5 or 6-benzothienyl; benzimidazolyl, in particular 2,5or 6-benzimidazolyl; benzothiazolyl, in particular 5 or6-benzothiazolyl; purinyl, in particular 2 or 8-purinyl; quinolinyl, inparticular 2,3,6 or 7-quinolinyl; isoquinolinyl, in particular 3,6 or7-isoquinolinyl; cinnolinyl, in particular 6 or 7-cinnolinyl;phthalazinyl, in particular 6 or 7-phthalazinyl; quinazolinyl, inparticular 2,6 or 7-quinazolinyl; quinoxalinyl, in particular 2 or6-quinoxalinyl; 1,8-naphthyridinyl, in particular 1,8-naphthyridin-2,3,6or 7-yl; pteridinyl, in particular 2,6 or 7-pteridinyl; and indenyl, inparticular 1,2,3,5 or 5-indenyl.

Pharmaceutically Acceptable Salts

The 3-substituted quinudidine derivatives of the invention may beprovided in any form suitable for the intended administration. Suitableforms include pharmaceutically (i.e. physiologically) acceptable salts,and pre- or prodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate derived, the phthalate,the salicylate, the sorbate, the stearate, the succinate, the tartrate,the toluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Metal salts of a chemical compound of the invention include alkali metalsalts, such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts(aza-onium salts). Preferred aza-onium salts include the alkyl-oniumsalts, in particular the methyl- and ethyl-onium salts; thecycloalkyl-onium salts, in particular the cyclopropyl-onium salts; andthe cycloalkylalkyl-onium salts, in particular thecyclopropyl-methyl-onium salts.

Steric Isomers

The 3-substituted quinuclidine derivatives of the invention may exist in(+) and (−) forms as well as in racemic forms (±). The racemates ofthese isomers and the individual isomers themselves are within the scopeof the present invention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I-(tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Methods of Preparation

The 3-substituted quinuclidine derivatives of the invention may beprepared by conventional methods for chemical synthesis, e.g. thosedescribed in the working examples. The starting materials for theprocesses described in the present application are known or may readilybe prepared by conventional methods from commercially availablechemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

The 3-substituted quinuclidine derivatives of the present invention showuseful biological properties. In particular they are found to becholinergic ligands at the nicotinic acetylcholine receptors (nAChR),and/or modulators of the monoamine receptors, in particular the biogenicamine transporters such as the serotonin receptor (5-HTR), the dopaminereceptor (DAR) and the norepinephrine receptor (NER), and of thebiogenic amine transporters for serotonin (5-HT), dopamine (DA) andnorepinephrine (NE). The compounds of the present invention may inparticular be agonists, partial agonists, antagonists and allostericmodulators of the receptor.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or conditions as diverse as CNSrelated diseases, PNS related diseases, diseases related to smoothmuscle contraction, endocrine disorders, diseases related toneuro-degeneration, diseases related to inflammation, pain, andwithdrawal symptoms caused by the termination of abuse of chemicalsubstances.

In a preferred embodiment the compounds of the invention are used forthe treatment of diseases, disorders, or conditions relating to thecentral nervous system. Such diseases or disorders includes anxiety,cognitive disorders, learning deficit, memory deficits and dysfunction,Alzheimer's disease, attention deficit, attention deficit hyperactivitydisorder (ADHD), Parkinson's disease, Huntington's disease, AmyotrophicLateral Sclerosis, Gilles de la Tourette's syndrome, psychosis,depression, mania, manic depression, schizophrenia, obsessive compulsivedisorders (OCD), panic disorders, eating disorders such as anorexianervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia,senile dementia, periferic neuropathy, autism, dyslexia, tardivedyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome,social phobia, sleeping disorders, pseudodementia, Ganser's syndrome,pre-menstrual syndrome, late luteal phase syndrome, chronic fatiguesyndrome, mutism, trichotillomania, and jet-lag.

In a preferred embodiment diseases, disorders, or conditions relating tothe central nervous system for which the compounds of the invention areused are cognitive disorders, psychosis, schizophrenia and/ordepression.

In another preferred embodiment the compounds of the invention may beuseful for the treatment of diseases, disorders, or conditionsassociated with smooth muscle contractions, including convulsivedisorders, angina pectoris, premature labour, convulsions, diarrhoea,asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

In yet another preferred embodiment the compounds of the invention maybe useful for the treatment of endocrine disorders, such asthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In still another preferred embodiment the compounds of the invention maybe useful for the treatment of neurodegenerative disorders, includingtransient anoxia and induced neuro-degeneration.

In even another preferred embodiment the compounds of the invention maybe useful for the treatment of inflammatory diseases, disorders, orconditions, including inflammatory skin disorders such as acne androsacea, Chron's disease, inflammatory bowel disease, ulcerativecolitis, and diarrhoea.

In still another preferred embodiment the compounds of the invention maybe useful for the treatment of mild, moderate or even severe pain ofacute, chronic or recurrent character, as well as pain caused bymigraine, postoperative pain, and phantom limb pain. The pain may inparticular be neuropathic pain, chronic headache, central pain, painrelated to diabetic neuropathy, to post therapeutic neuralgia, or toperipheral nerve injury.

Finally the compounds of the invention may be useful for the treatmentof withdrawal symptoms caused by termination of use of addictivesubstances. Such addictive substances include nicotine containingproducts such as tobacco, opioids such as heroin, cocaine and morphine,benzodiazepines and benzodiazepine-like drugs, and alcohol. Withdrawalfrom addictive substances is in general a traumatic experiencecharacterised by anxiety and frustration, anger, anxiety, difficultiesin concentrating, restlessness, decreased heart rate and increasedappetite and weight gain.

In this context “treatment” covers treatment, prevention, prophylacticsand alleviation of withdrawal symptoms and abstinence as well astreatment resulting in a voluntary diminished intake of the addictivesubstance.

In another aspect, the compounds of the invention are used as diagnosticagents, e.g. for the identification and localisation of nicotinicreceptors in various tissues.

Neuroimaging

The 3-substituted quinuclidine derivatives of the invention may beuseful as diagnostic tools or monitoring agents in various diagnosticmethods, and in particular for in vivo receptor imaging (neuroimaging).

In another aspect of the invention a method for the non-invasivedetermination of the distribution of a tracer compound inside a whole,intact living animal or human body using a physical detection method isprovided. According to this method a tracer compound is a compound ofthe invention, or any of its enantiomers or any mixture thereof, or apharmaceutically acceptable salt thereof, in labelled or unlabelledform.

In a preferred embodiment the physical detection method is selected fromPET, SPECT; MRS, MRI, CAT, or combinations thereof.

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

The labelled compound of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ¹²³I, ¹²⁵I, ¹³¹I, ³H and^(99m)Tc.

An examples of commercially available labelling agents, which can beused in the preparation of the labelled compounds of the presentinvention is [¹¹C]O₂, ¹⁸F and NaI with different isotopes of Iodine.

In particular [C¹¹]O₂ may be converted to a [¹¹C]-methylating agent,such as [¹¹C]H₃I or [¹¹C]-methyl triflate.

The tracer compound can be selected in accordance with the detectionmethod chosen.

In one preferred embodiment, the labelled or unlabelled compound of theinvention can be detected by a suitable spectroscopic method, inparticular UV spectroscopy and/or fluorescence spectroscopy.

In anther preferred embodiment, the compounds of the invention arelabelled by incorporation of a isotope into the molecule, which may inparticular be an isotope of the naturally occurring atoms includingdeuterium, tritium, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F, the isotopeincorporation may be measured by conventional scintillation countingtechniques.

In a third preferred embodiment, the physical method for detecting saidtracer compound of the present invention is selected from PositionEmission Tomography (PET), Single Photon Imaging Computed Tomography(SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic ResonanceImaging (MRI), and Computed Axial X-ray Tomography (CAT), orcombinations thereof.

Before conducting the method of the present invention, a diagnosticallyeffective amount of a labelled or unlabelled compound of the inventionis administered to a living body, including a human.

The diagnostically effective amount of the labelled or unlabelledcompound of the invention to be administered before conducting thein-vivo method for the present invention is within a range of from 0.1ng to 100 mg per kg body weight, preferably within a range of from 1 ngto 10 mg per kg body weight.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of a3-substituted quinuclidine derivatives of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the 3-substituted quinuclidine derivatives ofthe invention, or a pharmaceutically acceptable salt or derivativethereof, together with one or more pharmaceutically acceptable carrierstherefor, and, optionally, other therapeutic and/or prophylacticingredients, know and used in the art. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route which suite the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition may be prepared bythe skilled person using standard and conventional techniquesappropriate to the desired formulation. When desired, compositionsadapted to give sustained release of the active ingredient may beemployed.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired herapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

The compounds of the present invention are valuable nicotinicacetylcholine receptor modulators and therefore useful for the treatmentof a range of ailments involving cholinergic dysfunction as well as arange of disorders responsive to the action of nicotinic acetylcholinereceptor modulators as well as the serotonin receptor.

Therefore, in another aspect the invention relates to the a method ofthe treatment or alleviation of a disease, disorder or condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to the action of a nicotinic acetylcholinereceptor modulator, which method comprises the step of administering tosuch a living animal body, including a human, in need thereof atherapeutically effective amount of the chemical compound of theinvention.

The preferred indications for the method of the invention are thosestated above.

In the context of this invention the term “treating” covers treatment,prevention, prophylaxis or alleviation, and the term “disease” coversillnesses, diseases, disorders and conditions related to the disease inquestion.

It is at present contemplated that a suitable dosage lies within therange of from about 0.1 to about 500 milligram of active substancedaily, more preferred of from about 10 to about 70 milligram of activesubstance daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 Preparatory Example

General: All reactions involving air sensitive reagents or intermediateswere performed under nitrogen and in anhydrous solvents. Magnesiumsulphate was used as drying agent in the workup-procedures and solventswere evaporated under reduced pressure.

(±)-3-[Amino-1-(2-aminophenyl)]-quinuclidine (Intermediate compound)

A mixture of (±)-3-[amino-1-(2-nitrophenyl)]-quinuclidine (2.99 g, 12.5mmol), palladium on carbon (500 mg, 10%, 50% water) and ethanol (50 ml)was stirred under hydrogen for 3.5 hours. The crude mixture was filteredthrough celite and was evaporated. The title compound was compound wasisolated as an oil in quantitative yield (2.81 g, 12.5 mmol).

(±)-3-[Amino-1-(2-nitrophenyl)]-quinuclidine (Intermediate compound)

A mixture of (±)-3-aminoquinuclidine dihydrochloride (3.0 g 15.1 mmol)1-fluoro-2-nitrobenzene (1.6 ml, 15.1 mmol), cecium carbonate (9.84 g,30.2 mmol) and dimethylsulfoxide (5.0 ml) was stirred at 100° C. for 2hours. Aqueous sodium hydroxide (50 ml, 1 M) was added followed byextraction with dichloromethane (2×50 ml). The combined organic phaseswere purified by chromatography on silica gel with dichloromethane,methanol and conc. ammonia (89:10:1) gave the title compound as an oil.Yield 2.99 g (80%).

Method A

(±)-3-(1-Benzimidazolyl)-quinuclidine fumaric acid salt (Compound A1)

A mixture of (±)-3-[amino-1-(2-aminophenyl)]-quinuclidine (2.81 g, 12.5mmol), formic acid (10 ml) and formaldehyde (10 ml) was stirred atreflux for 1.5 hours. The mixture was evaporated. Aqueous sodiumhydroxide (100 ml, 1 M) was added to the mixture followed by extractionwith dichloromethane (3×50 ml). The combined organic phases werepurified by chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) and gave the title compound. Yield 0.14 g(5%).

The corresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 180.0-181.1° C.

(±)-3-(2-Trifluoromethyl-1-benzimidazolyl)-quinuclidine fumaric acidsalt (Compound A2)

Was prepared from (±)-3-[amino-1-(2-aminophenyl)]-quinuclidine by MethodA, using trifluoroacetic anhydride (instead of the mixture offormaldehyde and formic acid). Mp 188.4-189.4° C.

(±)-3-(5-Trifluoromethyl-1-benzimidazolyl)-quinuclidine fumaric acidsalt (Compound A3)

Was prepared from(±)-3-[amino-1-(5-trifluoromethyl-2-aminophenyl)]-quinuclidine by MethodA. Mp 185.5-187.1° C.

Method B

3-(3-Indolyl)quinuclidine-2-ene fumaric acid salt (Compound B1)

A mixture of 3-quinuclidinone (2.0, 16.0 mmol), indole (1.87 g, 16.0mmol), sodium methoxide (1.73 g, 32 mmol) and methanol (40 ml) wasstirred at reflux for 70 hours. The mixture was evaporated. Aqueoussodium hydroxide (100 ml, 1 M) was added followed by extraction withdichloromethane (3×50 ml). The combined organic phases were purified bychromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound as an oil. The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1) saturated with fumaric acid. Yield 0.61 g (11%). Mp 138.1-138.8°C.

3-(5-Bromo-3-indolyl)quinuclidine-2-ene fumaric acid salt (Compound B2)

Was prepared according to Method B. Mp 271-275° C.

3-(5-Methoxy-3-indolyl)-quinuclidine-2-ene fumaric acid salt (CompoundB3)

Was prepared according to Method B. Mp 216-217° C.

3-(5-Phenyl-3-indolyl)-quinuclidine-2-ene fumaric acid salt (CompoundB4)

A mixture of 3-(5-bromo-3-indolyl)-quinuclidine-2-ene (2.18 g, 7.19mmol), phenylboronic acid (1.31 g, 10.8 mmol), potassium carbonate (2.99g, 21.6 mmol), 1,3-propandiol (1.56 ml, 21.6 mmol), palladacycle (67 mg,0.072 mmol), tri-t-butylphosphine (14.5 mg, 0.072 mmol), palladiumacetate (16 mg, 0.072 mmol) and 1.4-dioxane was stirred at reflux for 15hours. The mixture was evaporated. Aqueous sodium hydroxide (100 ml, 1M) was added followed by extraction with dichloromethane (3×50 ml). Thecombined organic phases were purified by chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1) gave thetitle compound. The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid.Yield 2.09 g (70%). Decomp. 246° C.

(±)-3-(1-Benzotriazolyl)-quinuclidine fumaric acid salt (Compound B5)

A mixture of (±)-3-[amino-1-(2-aminophenyl)]-quinuclidine (6.27 g, 28.9mmol), water (60 ml), acetic acid (20 ml), concentrated hydrochloricacid (1 ml) and sodium nitrite (2.19 g, 31.7 mmol) was stirred at 80° C.for 2 hours. The mixture was allowed to reach room temperature. Aqueoussodium hydroxide (100 ml, 1 M) was added followed by extraction withdichloromethane (3×50 ml). The combined organic phases were purified bychromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound as an oil. The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1) saturated with fumaric acid. Yield 2.59 g (26%). Mp 188.4-189.4°C.

Example 2

In Vitro Inhibition of ³H-α-Bungarotoxine Binding in Rat Brain

In this example the affinity of the compounds of the invention forbinding to α₇-subtype of nicotinic receptors is determined.

α-Bungarotoxine is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus. It has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.

³H-α-Bungarotoxine labels nicotinic acetylcholine receptors formed bythe α₇ subunit isoform found in brain and the α₁ isoform in theneuromuscular junction.

Tissue Preparation

Preparations are performed at 0-4° C. Cerebral cortices from male Wistarrats (150-250 g) are homogenised for 10 seconds in 15 ml of 20 mM Hepesbuffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂(pH 7.5) using an Ultra-Turrax homogeniser. The tissue suspension issubjected to centrifugation at 27,000×g for 10 minutes. The supernatantis discarded and the pellet is washed twice by centrifugation at27,000×g for 10 minutes in 20 ml of fresh buffer, and the final pelletis then re-suspended in fresh buffer containing 0.01% BSA (35 ml per gof original tissue) and used for binding assays.

Assay

Aliquots of 500 μl of homogenate are added to 25 μl of test solution and25 μl of ³H-α-bungarotoxine (2 nM, final concentration) and mixed andincubated for 2 hours at 37° C. Non-specific binding is determined using(−)-nicotine (1 mM, final concentration). After incubation, the samplesare added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poureddirectly onto Whatman GF/C glass fibre filters (pre-soaked in 0.1% PEIfor at least 6 hours) under suction, and immediately washed with 2×5 mlice-cold buffer.

The amount of radioactivity on the filters is determined byconventional-liquid scintillation counting. Specific binding is totalbinding minus non-specific binding.

The test value is given as an IC₅₀ (the concentration of the testsubstance which inhibits the specific binding of ³H-α-bungarotoxin by50%).

The results of these experiments are presented in Table 1 below. TABLE 1Inhibition of ³H-α-Bungarotoxine Binding Compound IC₅₀ (μM) A1 0.40

1. A 3-substituted quinuclidine derivative represented by Formula I:

wherein - - - - represents an optional double bond; and R′ represents anindolyl group, a benzimidazolyl group or a benzotriazolyl group, whichheteroaryl group is optionally substituted one or more times with alkyl,cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkenoxy,alkoxyalkenyl, alkynyl, alkoxyalkynyl, alkynoxy, alkylthio, alkylseleno,methylenedioxy, trifluoromethanesulfonyloxy, halo, haloalkyl, hydroxy,haloalkoxy, cyano, amino, nitro, oxime, alkyloxime, acyloxime, aryl,heteroaryl, and/or a group of the formula —(CO)R⁴, —COOR⁴, —O(CO)R⁴,—CONR³R⁴, —NH—CO₂R³, —NHCO—R³ or —OCO—NR³R⁴; in which formulas R³ and R⁴independently of one another represents hydrogen or alkyl; any of itsenantiomers or any mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an aza-onium-salt thereof.
 2. The3-substituted quinuclidine derivative of claim 1, represented by FormulaII:

wherein - - - - represents an optional double bond; and R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, alkoxycycloalkyl,cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkoxyalkenyl, alkynyl,alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano, amino, nitro, phenyl,and/or a group of the formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³,—NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulas R² and R³independently of each another represents hydrogen or alkyl.
 3. The3-substituted quinuclidine derivative of claim 2, represented by FormulaIII:

wherein R¹ and R², independently of one another, represent hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl,alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano,amino, nitro, phenyl, and/or a group of the formula —(CO)R³, —COOR³,—O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulasR² and R³ independently of each another represents hydrogen or alkyl. 4.The quinuclidine derivative of claim 1, wherein R¹ and R², independentlyof one another, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, hydroxyalkoxy, halo, haloalkyl, hydroxy,haloalkoxy, cyano, amino, nitro or phenyl.
 5. The quinuclidinederivative of claim 1, wherein R¹ and R², independently of one another,represent hydrogen, alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano,amino, nitro or phenyl.
 6. The quinuclidine derivative of claim 1,wherein one of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.
 7. The quinuclidine derivative of claim 3, which is3-(3-Indolyl)-quinuclidine-2-ene;3-(5-Bromo-3-indolyl)-quinuclidine-2-ene;3-(5-Methoxy-3-indolyl)-quinuclidine-2-ene;3-(5-Phenyl-3-indolyl)-quinuclidine-2-ene; any of its enantiomers or anymixture of enantiomers, or a pharmaceutically acceptable salt thereof,or an aza-onium-salt thereof.
 8. The 3-substituted quinuclidinederivative of claim 1, represented by Formula IV:

wherein - - - - represents an optional double bond; and R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, alkoxycycloalkyl,cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkoxyalkenyl, alkynyl,alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano, amino, nitro, phenyl,and/or a group of the formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³,—NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulas R² and R³independently of each another represents hydrogen or alkyl.
 9. The3-substituted quinuclidine derivative of claim 8, represented by FormulaV:

wherein R¹ and R², independently of one another, represent hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl,alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano,amino, nitro, phenyl, and/or a group of the formula —(CO)R³, —COOR³,—O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulasR² and R³ independently of each another represents hydrogen or alkyl.10. The quinuclidine derivative of claim 8, wherein R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo, haloalkyl,hydroxy, haloalkoxy, cyano, amino, nitro or phenyl.
 11. The quinuclidinederivative of claim 8, wherein R¹ and R², independently of one another,represent hydrogen, alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano,amino, nitro or phenyl.
 12. The quinuclidine derivative of claim 8,wherein one of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.
 13. The quinuclidine derivative of claim 9, which is(±)-3-(1-Benzimidazolyl)-quinuclidine;(±)-3-(2-Trifluoromethyl-1-benzimidazolyl)-quinuclidine; or(±)-3-(5-Trifluoromethyl-1-benzimidazolyl)-quinuclidine; any of itsenantiomers or any mixture of enantiomers, or a pharmaceuticallyacceptable salt thereof, or an aza-onium-salt thereof.
 14. The3-substituted quinuclidine derivative of claim 1, represented by FormulaVI:

wherein - - - - represents an optional double bond; and R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, alkoxycycloalkyl,cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkoxyalkenyl, alkynyl,alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano, amino, nitro, phenyl,and/or a group of the formula —(CO)R³, —COOR³, —O(CO)R³, —CONR²R³,—NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulas R² and R³independently of each another represents hydrogen or alkyl.
 15. The3-substituted quinuclidine derivative of claim 14, represented byFormula VII:

wherein R¹ and R², independently of one another, represent hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl,alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano,amino, nitro, phenyl, and/or a group of the formula —(CO)R³, —COOR³,—O(CO)R³, —CONR²R³, —NH—CO₂R², —NHCO—R² or —OCO—NR²R³; in which formulasR² and R³ independently of each another represents hydrogen or alkyl.16. The quinuclidine derivative of claim 14, wherein R¹ and R²,independently of one another, represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo, haloalkyl,hydroxy, haloalkoxy, cyano, amino, nitro or phenyl.
 17. The quinuclidinederivative of claim 14, wherein R¹ and R², independently of one another,represent hydrogen, alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano,amino, nitro or phenyl.
 18. The quinuclidine derivative of claim 14,wherein one of R¹ and R² represents hydrogen, and the other of R¹ and R²represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitroor phenyl.
 19. The quinuclidine derivative of claim 15, which is(±)-3-(1-Benzotriazolyl)-quinuclidine; any of its enantiomers or anymixture of enantiomers, or a pharmaceutically acceptable salt thereof,or an aza-onium-salt thereof.
 20. A pharmaceutical compositioncomprising a therapeutically effective amount of a 3-substitutedquinuclidine derivative of claim 1, any of its enantiomers or anymixture of enantiomers, or a pharmaceutically acceptable salt thereof,together with at least one pharmaceutically acceptable carrier ordiluent.
 21. A method of treatment, prevention or alleviation of adisease or a disorder or a condition of a living animal body, includinga human, which disorder, disease or condition is responsive tomodulation of cholinergic receptors and/or monoamine receptors, whichmethod comprises the step of administering to such a living animal bodyin need thereof a therapeutically effective amount of a 3-substitutedquinuclidine derivative of claim
 1. 22. The method according to claim21, wherein the disease, disorder or condition relates to the centralnervous system.
 23. The method according to claim 22, wherein thedisease, disorder or condition is anxiety, cognitive disorders, learningdeficit, memory deficits and dysfunction, Alzheimer's disease, attentiondeficit, attention deficit hyperactivity disorder (ADHD), Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles dela Tourette's syndrome, psychosis, depression, mania, manic depression,schizophrenia, obsessive compulsive disorders (OCD), panic disorders,eating disorders such as anorexia nervosa, bulimia and obesity,narcolepsy, nociception, AIDS-dementia, senile dementia, perifericneuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia,epilepsy, bulimia, post-traumatic syndrome, social phobia, sleepingdisorders, pseudodementia, Ganser's syndrome, pre-menstrual syndrome,late luteal phase syndrome, chronic fatigue syndrome, mutism,trichotillomania, and jet-lag.
 24. The method according to claim 21,wherein the disease, disorder or condition are associated with smoothmuscle contractions, including convulsive disorders, angina pectoris,premature labour, convulsions, diarrhoea, asthma, epilepsy, tardivedyskinesia, hyperkinesia, premature ejaculation, and erectiledifficulty.
 25. The method according to claim 21, wherein the disease,disorder or condition is related to the endocrine system, such asthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
 26. Themethod according to claim 21, wherein the disease, disorder or conditionis a neurodegenerative disorders, including transient anoxia and inducedneuro-degeneration.
 27. The method according to claim 21, wherein thedisease, disorder or condition is an inflammatory disorder, includinginflammatory skin disorders such as acne and rosacea, Chron's disease,inflammatory bowel disease, ulcerative colitis, and diarrhoea.
 28. Themethod according to claim 21, wherein the disease, disorder or conditionis mild, moderate or even severe pain of acute, chronic or recurrentcharacter, pain caused by migraine, postoperative pain, phantom limbpain, neuropathic pain, chronic headache, central pain, pain related todiabetic neuropathy, to post therapeutic neuralgia, or to peripheralnerve injury.
 29. The method according to claim 21, wherein the disease,disorder or condition is associated with withdrawal symptoms caused bytermination of use of addictive substances, including nicotinecontaining products such as tobacco, opioids such as heroin, cocaine andmorphine, benzodiazepines and benzodiazepine-like drugs, and alcohol.30. (canceled)